tbuckley/cabot-search huggingface dataset:
The new direction of drug development: Degradation of undruggable targets through targeting chimera technology
Authors: Xuewu Liang, Hairu Ren, Fengyang Han, Renwen Liang, Jiayan Zhao, Hong Liu
Journal: Medicinal Research Reviews (2023)

Abstract Imbalances in protein and noncoding RNA levels in vivo lead to the occurrence of many diseases. In addition to the use of small molecule inhibitors and agonists to restore these imbalances, recently emerged targeted degradation technologies provide a new direction for disease treatment. Targeted degradation technology directly degrades target proteins or RNA by utilizing the inherent degradation pathways, thereby eliminating the functions of pathogenic proteins (or RNA) to treat diseases. Compared with traditional therapies, targeted degradation technology which avoids the principle of traditional inhibitor occupation drive, has higher efficiency and selectivity, and widely expands the range of drug targets. It is one of the most promising and hottest areas for future drug development. Herein, we systematically introduced the in vivo degradation systems applied to degrader design: ubiquitin–proteasome system, lysosomal degradation system, and RNA degradation system. We summarized the development progress, structural characteristics, and limitations of novel chimeric design technologies based on different degradation systems. In addition, due to the lack of clear ligand‐binding pockets, about 80% of disease‐associated proteins cannot be effectively intervened with through traditional therapies. We deeply elucidated how to use targeted degradation technology to discover and design molecules for representative undruggable targets including transcription factors, small GTPases, and phosphatases. Overall, this review provides a comprehensive and systematic overview of targeted degradation technology‐related research advances and a new guidance for the chimeric design of undruggable targets.
B‐cell lymphoma‐2 family proteins in the crosshairs: Small molecule inhibitors and activators for cancer therapy
Authors: Qineng Gong, Haojie Wang, Mi Zhou, Lu Zhou, Renxiao Wang, Yan Li
Journal: Medicinal Research Reviews (2023)

Abstract The B‐cell lymphoma‐2 (BCL‐2) family of proteins plays a crucial role in the regulation of apoptosis, offering a dual mechanism for its control. Numerous studies have established a strong association between gene disorders of these proteins and the proliferation of diverse cancer cell types. Consequently, the identification and development of drugs targeting BCL‐2 family proteins have emerged as a prominent area in antitumor therapy. Over the last two decades, several small‐molecules have been designed to modulate the protein–protein interactions between anti‐ and proapoptotic BCL‐2 proteins, effectively suppressing tumor growth and metastasis in vivo. The primary focus of research has been on developing BCL‐2 homology 3 (BH3) mimetics to target antiapoptotic BCL‐2 proteins, thereby competitively releasing proapoptotic BCL‐2 proteins and restoring the blocked intrinsic apoptotic program. Additionally, for proapoptotic BCL‐2 proteins, exogenous small molecules have been explored to activate cell apoptosis by directly interacting with executioner proteins such as BCL‐2‐associated X protein (BAX) or BCL‐2 homologous antagonist/killer protein (BAK). In this comprehensive review, we summarize the inhibitors and activators (sensitizers) of BCL‐2 family proteins developed over the past decades, highlighting their discovery, optimization, preclinical and clinical status, and providing an overall landscape of drug development targeting these proteins for therapeutic purposes.
Assessing Predictability of Pathologic Lymph Node Regression for Recurrence and Survival in Esophageal Adenocarcinoma
Authors: Ryan Sun, Jingyi Liu, Lee-Jen Wei
Journal: Journal of Clinical Oncology (2023)

Moore et al 1 conducted an extensive study to evaluate if lymph node (LN) classification would predict the timings of patient's survival and disease recurrence via the standard Cox regression adjusting for confounders including primary tumor regression.The discriminatory ability of different LN response classifications to predict event times was evaluated using akaike information criterion (AIC) and Harrell C-index.The authors state that a model with higher C-index and lower AIC values was considered to have better discriminatory ability.There are several issues in the article that may need to be clarified.
Efficacy and Safety of Disitamab Vedotin in Patients With Human Epidermal Growth Factor Receptor 2–Positive Locally Advanced or Metastatic Urothelial Carcinoma: A Combined Analysis of Two Phase II Clinical Trials
Authors: Xinan Sheng, Lin Wang, Zhisong He, Yanxia Shi, Hong Luo, Weiqing Han, Xin Yao, Benkang Shi, Jiyan Liu, Changlu Hu, Ziling Liu, Hongqian Guo, Guohua Yu, Zhigang Ji, Jianming Ying, Yun Ling, Shiying Yu, Yi Hu, Jianming Guo, Jianmin Fang, Aiping Zhou, Jun Guo
Journal: Journal of Clinical Oncology (2023)

To evaluate the efficacy and safety of disitamab vedotin (DV, RC48-ADC), a novel humanized anti-human epidermal growth factor receptor 2 (HER2) antibody conjugated with monomethyl auristatin E, in patients with HER2-positive locally advanced or metastatic urothelial carcinoma (UC) refractory to standard or regular therapies.
Selective Personalized RadioImmunotherapy for Locally Advanced Non–Small-Cell Lung Cancer Trial (SPRINT)
Authors: Nitin Ohri, Shruti Jolly, Benjamin T. Cooper, Rafi Kabarriti, William R. Bodner, Jonathan Klein, Chandan Guha, Shankar Viswanathan, Elaine Shum, Joshua K. Sabari, Haiying Cheng, Rasim A. Gucalp, Enrico Castellucci, Angel Qin, Shirish M. Gadgeel, Balazs Halmos
Journal: Journal of Clinical Oncology (2023)

PURPOSE Standard therapy for locally advanced non–small-cell lung cancer (LA-NSCLC) is concurrent chemoradiotherapy followed by adjuvant durvalumab. For biomarker-selected patients with LA-NSCLC, we hypothesized that sequential pembrolizumab and risk-adapted radiotherapy, without chemotherapy, would be well-tolerated and effective. METHODS Patients with stage III NSCLC or unresectable stage II NSCLC and an Eastern Cooperative Oncology Group performance status of 0-1 were eligible for this trial. Patients with a PD-L1 tumor proportion score (TPS) of ≥50% received three cycles of induction pembrolizumab (200 mg, once every 21 days), followed by a 20-fraction course of risk-adapted thoracic radiotherapy (55 Gy delivered to tumors or lymph nodes with metabolic volume exceeding 20 cc, 48 Gy delivered to smaller lesions), followed by consolidation pembrolizumab to complete a 1-year treatment course. The primary study end point was 1-year progression-free survival (PFS). Secondary end points included response rates after induction pembrolizumab, overall survival (OS), and adverse events. RESULTS Twenty-five patients with a PD-L1 TPS of ≥50% were enrolled. The median age was 71, most patients (88%) had stage IIIA or IIIB disease, and the median PD-L1 TPS was 75%. Two patients developed disease progression during induction pembrolizumab, and two patients discontinued pembrolizumab after one infusion because of immune-related adverse events. Using RECIST criteria, 12 patients (48%) exhibited a partial or complete response after induction pembrolizumab. Twenty-four patients (96%) received definitive thoracic radiotherapy. The 1-year PFS rate is 76%, satisfying our efficacy objective. One- and 2-year OS rates are 92% and 76%, respectively. The most common grade 3 adverse events were colitis (n = 2, 8%) and esophagitis (n = 2, 8%), and no higher-grade treatment-related adverse events have occurred. CONCLUSION Pembrolizumab and risk-adapted radiotherapy, without chemotherapy, are a promising treatment approach for patients with LA-NSCLC with a PD-L1 TPS of ≥50%.
Natural language processing system for rapid detection and intervention of mental health crisis chat messages
Authors: Akshay Swaminathan, Iván López, Rafael Antonio Garcia Mar, Tyler Heist, Tom McClintock, Kaitlin Caoili, Madeline Grace, Matthew Rubashkin, Michael N. Boggs, Jonathan H. Chen, Olivier Gevaert, David Mou, Matthew K. Nock
Journal: npj Digital Medicine (2023)

Patients experiencing mental health crises often seek help through messaging-based platforms, but may face long wait times due to limited message triage capacity. Here we build and deploy a machine-learning-enabled system to improve response times to crisis messages in a large, national telehealth provider network. We train a two-stage natural language processing (NLP) system with key word filtering followed by logistic regression on 721 electronic medical record chat messages, of which 32% are potential crises (suicidal/homicidal ideation, domestic violence, or non-suicidal self-injury). Model performance is evaluated on a retrospective test set (4/1/21-4/1/22, N = 481) and a prospective test set (10/1/22-10/31/22, N = 102,471). In the retrospective test set, the model has an AUC of 0.82 (95% CI: 0.78-0.86), sensitivity of 0.99 (95% CI: 0.96-1.00), and PPV of 0.35 (95% CI: 0.309-0.4). In the prospective test set, the model has an AUC of 0.98 (95% CI: 0.966-0.984), sensitivity of 0.98 (95% CI: 0.96-0.99), and PPV of 0.66 (95% CI: 0.626-0.692). The daily median time from message receipt to crisis specialist triage ranges from 8 to 13 min, compared to 9 h before the deployment of the system. We demonstrate that a NLP-based machine learning model can reliably identify potential crisis chat messages in a telehealth setting. Our system integrates into existing clinical workflows, suggesting that with appropriate training, humans can successfully leverage ML systems to facilitate triage of crisis messages.
Current status of indocyanine green fluorescent angiography in assessing perfusion of gastric conduit and esophago-gastric anastomosis
Authors: Syed Nusrath, Prasanthi Kalluru, Srijan Shukla, Anvesh Dharanikota, Madhunarayana Basude, Pawan Jonnada, Muayyad Abualjadayel, Saleh Alabbad, Tanveer Ahmad Mir, Dieter C. Broering, KVVN Raju, Thammineedi Subramanyeshwar Rao, Yogesh Kumar Vashist
Journal: International Journal of Surgery (2023)

Anastomotic leak (AL) remains a significant complication after esophagectomy. Indocyanine green fluorescent angiography (ICG-FA) is a promising and safe technique for assessing gastric conduit (GC) perfusion intraoperatively. It provides detailed visualization of tissue perfusion and has demonstrated usefulness in esophageal surgery. GC perfusion analysis by ICG-FA is crucial in constructing the conduit and selecting the anastomotic site and enables surgeons to make necessary adjustments during surgery to potentially reduce ALs. However, anastomotic integrity involves multiple factors, and ICG-FA must be combined with optimization of patient and procedural factors to decrease AL rates. This review summarizes ICG-FA’s current applications in assessing esophago-gastric anastomosis perfusion, including qualitative and quantitative analysis and different imaging systems. It also explores how fluorescent imaging could decrease ALs and aid clinicians in utilizing ICG-FA to improve esophagectomy outcomes.
Comparison of the postoperative outcome with and without intraoperative leak testing for sleeve gastrectomy: a systematic review and meta-analysis of 469 588 cases
Authors: Longyin Ma, Zhenguo Gao, Heng Luo, Shien Kou, Yu Lei, Victor Jia, Ke Lan, Subbiah Sankar, Jiani Hu, Yunhong Tian
Journal: International Journal of Surgery (2023)

Objective: Postoperative staple line leakage after sleeve gastrectomy is a rare but serious complication. Many surgeons routinely test anastomosis with an intraoperative leak test as part of the sleeve gastrectomy procedure. This meta-analysis aims to determine whether an intraoperative leak test plays a role in reducing the rate of postoperative staple line related complications in patients who underwent sleeve gastrectomy. Methods: We searched the PubMed, Web of science, the Cochrane Library and Clinical Trials.gov databases for clinical studies assessing the application of intraoperative leak test (IOLT) in sleeve gastrectomy. The primary endpoint was the development of postoperative staple line leakage. Secondary endpoints included the postoperative bleeding, 30 days mortality rates, and 30 days readmission rates. Results: Six studies totaling 469,588 patients met the inclusion criteria. Our review found that the Staple line leakage (SLL) rate was 0.38% (1,221/ 324,264) in the IOLT group and 0.31% (453/ 145,324) in the no intraoperative leak test (NIOLT) group. Postoperative staple line leakage decreased in the NIOLT group compared with the IOLT group (OR=1.27; 95%CI 1.14 to 1.42, P =0.000). Postoperative bleeding was fewer in the IOLT group than that in the NIOLT group (OR 0.79; 95% CI 0.72 to 0.87, P =0.000). There was no significant difference between the IOLT group and the NIOLT group regarding 30 days mortality rates and 30 days readmission rates ( P ＞0.05). Conclusion: IOLT was correlated with an increase in staple line leakage when included as a part of the sleeve gastrectomy procedure. However, IOLT was associated with a lower rate of postoperative bleeding. Thus, IOLT should be considered in sleeve gastrectomy in the situation of suspected postoperative bleeding.
A novel laparoscopic pancreaticoduodenal training model: optimization of the learning curve and simplification of postoperative complications
Authors: Yichen Tang, Xuehui Peng, Yonggang He, Jing Li, Lu Zheng, Xiaobing Huang
Journal: International Journal of Surgery (2023)

Purpose: Laparoscopic pancreaticoduodenectomy requires a long learning curve. A preoperative training system was established to optimize the surgeons’ learning curve and reduce the incidence rate of complications at the beginning of the curve. Methods: The laparoscopic pancreaticojejunostomy model, and choledochojejunostomy and gastrojejunostomy training systems were developed, and corresponding evaluation systems were also defined. Surgeons B and C performed laparoscopic pancreaticoduodenectomy after completing training session. Surgical outcomes, postoperative complications and their learning curves were analyzed. Results: Patients operated by surgeons B and C experienced shorter operative durations following training session than those in nontrained group (called A) ( P &lt;0.001). B and C began entering the inflection point at the 26th and 20th case in learning curve, respectively. The incidence of postoperative pancreatic fistula in group B was 3.3%, significantly lower than 13.1% in group A ( P =0.047). Patients in group B showed significantly lower incidence of biliary-enteric anastomosis leakage (0% vs. 8.2%, P =0.029) and Clavien–Dindo classification greater than or equal to 3 (3.3% vs. 14.8%, P =0.027) compared with those in group A. The incidence of surgical site infection in groups B (3.3%, P =0.004) and C (4.9%, P =0.012) was significantly lower than that in group A (19.7%). Moreover, the length of postoperative hospital stay was significantly shorter in groups B (12.5±5.9 days, P =0.002) and C (13.7±6.5 days, P =0.002) compared with group A (16.7±8.5 days). Conclusions: The laparoscopic pancreaticojejunostomy training model and evaluation system can shorten the operative duration, lower the risk of postoperative complications, and shorten the length of hospital stay.
Incorporation of protein induced by vitamin K absence or antagonist-II into transplant criteria expands beneficiaries of liver transplantation for hepatocellular carcinoma: a multicenter retrospective cohort study in China
Authors: Kai Wang, Libin Dong, Qian Lu, Zhe Yang, Xiaoli Fan, Fengqiang Gao, Wenwen Ge, Zhoucheng Wang, Zhisheng Zhou, Di Lu, Xuyong Wei, Qiang Wei, Li Zhuang, Lunxiu Qin, Qifa Ye, Jiayin Yang, Jiahong Dong, Shusen Zheng, Xiao Xu
Journal: International Journal of Surgery (2023)

In order to maximize the utilization of precious donor liver, precisely determining potential hepatocellular carcinoma (HCC) candidates who will benefit from liver transplantation (LT) is essential. As a crucial diagnostic biomarker for HCC, protein induced by vitamin K absence or antagonist-II (PIVKA-II) has become one of the key indicators for assessing tumor recurrence risk after LT. This study aims to investigate the role of PIVKA-II in recipient selection and prognostic stratification.
Artificial intelligence-aided detection for prostate cancer with multimodal routine health check-up data: an Asian multi-center study
Authors: Zijian Song, Wei Zhang, Qingchao Jiang, Longxin Deng, Le Du, Weiming Mou, Yancheng Lai, Wenhui Zhang, Yang Yang, Jasmine Lim, Kang Liu, Jae Young Park, Chi-Fai Ng, Teng Aik Ong, Qiang Wei, Lei Li, Xuedong Wei, Ming Chen, Zhixing Cao, Fubo Wang, Rui Chen
Journal: International Journal of Surgery (2023)

Background: The early detection of high-grade prostate cancer (HGPCa) is of great importance. However, the current detection strategies result in a high rate of negative biopsies and high medical costs. In this study, we aimed to establish an Asian Prostate Cancer Artificial intelligence (APCA) score with no extra cost other than routine health check-ups to predict the risk of HGPCa. Patients and methods: A total of 7476 patients with routine health checkup data who underwent prostate biopsies from January 2008 to December 2021 in eight referral centers in Asia were screened. After data pre-processing and cleaning, 5037 patients and 117 features were analyzed. Seven AI-based algorithms were tested for feature selection and seven AI-based algorithms were tested for classification, with the best combination applied for model construction. The APAC score was established in the CH cohort and validated in a multi-center cohort and in each validation cohort to evaluate its generalizability in different Asian regions. The performance of the models was evaluated using area under the receiver operating characteristic curve (ROC), calibration plot, and decision curve analyses. Results: Eighteen features were involved in the APCA score predicting HGPCa, with some of these markers not previously used in prostate cancer diagnosis. The area under the curve (AUC) was 0.76 (95% CI:0.74-0.78) in the multi-center validation cohort and the increment of AUC (APCA vs. PSA) was 0.16 (95% CI:0.13-0.20). The calibration plots yielded a high degree of coherence and the decision curve analysis yielded a higher net clinical benefit. Applying the APCA score could reduce unnecessary biopsies by 20.2% and 38.4%, at the risk of missing 5.0% and 10.0% of HGPCa cases in the multi-center validation cohort, respectively. Conclusions: The APCA score based on routine health checkups could reduce unnecessary prostate biopsies without additional examinations in Asian populations. Further prospective population-based studies are warranted to confirm these results.
The Dance Between Tumor Molecular Biology and Antitumor Immune Response
Authors: Kim A. Margolin
Journal: Clinical Cancer Research (2023)

Abstract When the cyclin kinase 4/6 inhibitor abemaciclib was sequenced with PD-1 blockade in mostly immunologically “cold” murine models, enhanced immune-mediated antitumor effects—including increased lifespan, recruitment of CD8 cells to tumor, reduction of regulatory T-cell and immunosuppressive cytokines in tumor, increased tumor antigen presentation, and broadening of the T-cell receptor repertoire—were achieved in both cutaneous and brain metastases. See related article by Nayyar et al., p. xxxx
Robotic pancreas surgery for pancreatic cancer
Authors: Sarah B. Hays, Aram E. Rojas, Melissa E. Hogg
Journal: International Journal of Surgery (2023)

Since the introduction of robotic pancreas surgery in the early 2000s, there has been significant increase in the adoption of the robot to perform complex pancreatic resections. However, utilization of the robot for pancreatic cancer has lagged behind due to concern for inferior oncologic outcomes. Furthermore, research in this field has previously been limited to small, single institution observational studies. Recent and ongoing randomized controlled trials in robotic distal pancreatectomy and robotic pancreatoduodenectomy have aimed to address concerns regarding the use of robotic techniques in pancreatic cancer. Together, these studies suggest similar, if not improved, outcomes with a robotic approach, including shorter hospital stays, expedited recovery with less postoperative complications, and equivalent resection rates, when compared to the standard open approaches. Additionally, surgical training in robotic pancreas surgery is of equal importance for patient safety. This review summarizes the available literature on the efficacy and safety of robotic pancreas surgery for pancreatic cancer, with specific focus on robotic distal pancreatectomy and robotic pancreatoduodenectomy.
Improving the nosology of Long COVID: it is not so simple
Authors: Leonard H Calabrese, Philip J Mease
Journal: Annals of the Rheumatic Diseases (2023)

Long COVID is a diagnostic label currently given to those suffering from a poorly understood state of incomplete recovery or who have development of a myriad of medically unexplained symptoms occurring in the wake of infection with SARS CoV-2 that is both poorly understood and controversial. Many of the features of one of the most common clinical endotypes of Long COVID are shared by a condition well familiar to all rheumatologists and one with a large body of epidemiologic, clinical and basic research accrued over many decades namely the syndrome of fibromyalgia. Some have recently suggested that Long COVID may merely be a new name for fibromyalgia and that this diagnosis is indeed the condition that many or most may be suffering from as a post infectious sequela. In this Viewpoint we argue that while the parallels between the clinical syndrome experienced by many of those currently labeled as Long COVID and fibromyalgia are strong we should be not too quick to rename the disorder. We further argue that relabeling Long COVID as fibromyalgia is clinically reductionistic and any such relabeling may be attended by harm in both the design and execution of a future research agenda as well to patients who may be inadvertently and unfortunately pejoritised by such labeling. We further explore the parallels and differences between Long COVID and fibromyalgia and outline areas of needed future research and care.
Response to: Correspondence on ‘2023 ACR/EULAR antiphospholipid syndrome classification criteria’ by Miro-Mur<i>et al</i>
Authors: Doruk Erkan, Medha Barbhaiya, Stephane Zuily, Maria Laura Bertolaccini, Rohan Willis, Katrien Devreese
Journal: Annals of the Rheumatic Diseases (2023)